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Adv Ther (2013) 30:1067–1085 DOI 10.1007/s12325-013-0071-y

REVIEW

The Dipeptidyl Peptidase (DPP)-4 Inhibitors for Type 2 Diabetes Mellitus in Challenging Patient Groups David Kountz

To view enhanced content go to www.advancesintherapy.com Received: August 9, 2013 / Published online: November 28, 2013 Ó The Author(s) 2013. This article is published with open access at Springerlink.com

ABSTRACT

groups and have demonstrated significant

Treating hyperglycemia is a critical aspect of

improvements in measures of hyperglycemia, with a good safety profile. Based on the current

managing type 2 diabetes mellitus (T2DM), but

evidence, it appears that the DPP-4 inhibitors

can be especially challenging in patients from vulnerable groups such as those with chronic

are worthy of consideration not only for the most straightforward patients with T2DM, but

kidney disease, African Americans, and older people. The dipeptidyl peptidase (DPP)-4

also for these vulnerable patients.

inhibitors are relatively new oral antidiabetes drugs that have been incorporated into treatment algorithms over the past few years and have also been studied in these vulnerable patients. Clinical trials with DPP-4 inhibitors have now been reported for all these patient Electronic supplementary material The online version of this article (doi:10.1007/s12325-013-0071-y) contains supplementary material, which is available to authorized users. D. Kountz (&) Jersey Shore University Medical Center, RutgersRobert Wood Johnson Medical School, 1945 State Route 33, PO Box 397, Neptune, NJ 07754-0397, USA e-mail: [email protected]

Keywords: African American; Chronic kidney disease; Dipeptidyl peptidase-4 Elderly; Type 2 diabetes mellitus

inhibitors;

INTRODUCTION The prevalence and incidence of diabetes are increasing worldwide, largely due to changing lifestyles characterized by reduced physical activity, rising obesity rates, and an aging population. In the US, diabetes is the leading cause of kidney failure, new cases of blindness, and non-traumatic lower limb amputations, and is a major cause of heart disease and stroke [1]. Diabetes currently affects 8.3% of the US population, some 25.8 million people [1], and type 2 diabetes mellitus (T2DM)

Enhanced content for Advances in Therapy articles is available on the journal web site: www.advancesintherapy.com

accounts for about 90–95% of all diagnosed diabetes cases in adults.

123

Adv Ther (2013) 30:1067–1085

1068

It is well documented that good glycemic

extensive testing in phase 3 clinical trials, these

control can positively influence much of the

agents have now been included in treatment

morbidity and mortality associated with T2DM [2]. To manage hyperglycemia, expert

recommendations in all major diabetes guidelines. This review will provide a brief

guidelines recommend treatment to a glycated hemoglobin (HbA1c) level of below 6.5% or

overview regarding the positioning of DPP-4 inhibitors in the context of major clinical

below 7.0%, with recognition of the need for

guidelines. Furthermore, since the majority of

individualization of treatment example, to minimize the

for of

patients in phase 3 trials are relatively young and healthy, an additional objective of this review is

hypoglycemia [2–4]. The percentage of US individuals with self-reported diabetes who

to consider the DPP-4 inhibitors for the treatment of T2DM in more vulnerable patient populations,

achieved an HbA1c level of \7% increased

namely those with chronic kidney disease (CKD),

from 44% in 1988–1994 to 52.5% in 2007–2010 [5]. Similarly, an observational

African Americans, and older people. Current guidelines for these patients, and the clinical trials

study of non-insulin–treated patients with T2DM from Spain (n = 2,266) indicated that

conducted with DPP-4 inhibitors in these groups, will be reviewed.

goals, risks

45% had suboptimal HbA1c based on the \7% criterion [6]. The International Diabetes Management Practices Study (IDMPS) of data

METHODS

from developing regions of Eastern Europe, Asia, and Latin America reported that 36.4% of

This was a non-systematic review of the

participants with T2DM achieved an HbA1c of \7% [7]. These data were consistent with those from an observational study in Taiwan in which the percentage of patients achieving the \7% goal increased from 32.4% in 2006 to 34.5% in 2011 [8]. Taken together, these findings suggest that there has been some success in putting guidelines into practice, but that approximately one-third to one-half of patients still fail to achieve HbA1c levels below 7.0% [5–8]. Furthermore, the progressive deterioration of b-cell function, irrespective of pharmacological interventions to treat hyperglycemia, leads to

literature. A search of English-language literature was performed using PubMed and without imposing any time limitations. Search terms included combinations of the following: ‘type 2 diabetes’, ‘DPP-4 inhibitors’, ‘chronic kidney disease’, ‘end-stage renal disease’, ‘renal impairment’, ‘African American’, and ‘elderly’. Articles and abstracts relevant to the subject were included. Bibliographies from retrieved articles were also searched for relevant articles. Additional references known to the author were also included. The analysis in this article is based on previously conducted studies, and does not involve any new studies of human or animal

an almost inevitable need for intensification of treatment [2]. There is, therefore, a recognized

subjects performed by any of the authors.

need for new therapeutic options that are well tolerated over the long term and have a durable

DPP-4 INHIBITORS

effect.

The DPP-4 inhibitors improve glycemic control mainly via potentiation of the incretin effect,

The dipeptidyl peptidase (DPP)-4 inhibitors are relatively new drugs that may help meet the need for these types of treatments, and following

123

that is, the postprandial augmentation of insulin secretion by the gastrointestinal

Adv Ther (2013) 30:1067–1085

1069

incretin hormones glucagon-like peptide (GLP)-

associated with a low risk of hypoglycemia, and

1 and gastric inhibitory polypeptide (GIP).

have a favorable weight profile [11]. As evidence

Increases in GLP-1 levels appear to account for the majority of the DPP-4 inhibitors’ effects [9].

accumulates for their effectiveness, the DPP-4 inhibitors have been incorporated into

In addition to enhancing glucose-dependent insulin secretion, GLP-1 suppresses glucose-

numerous guidelines available for the management of patients with T2DM. A

dependent glucagon secretion, inhibits gastric

consensus statement and algorithm issued by

emptying, and reduces appetite and food intake [10]. It has long been known that the incretin

the American Association of Clinical Endocrinologists (AACE) in 2013 describes

effect is blunted in patients with T2DM, generating interest in therapies that target the

several options for monotherapy and variations of combination therapy [4]. The

incretin system [10]. Native GLP-1 itself cannot

DPP-4

be used in therapy due to its rapid degradation by the DPP-4 enzyme, resulting in a half-life of

monotherapy options for patients with an entry level HbA1c of \7.5%. As with American

less than 2 min. Nevertheless, therapeutic approaches for enhancing incretin action have

Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD)

been

degradation-

recommendations, metformin is recommended

receptor agonists, and of GLP-1 indirectly by

as the first-line choice where not contraindicated. The AACE algorithm also

inhibition of DPP-4 [10]. Four DPP-4 inhibitors are approved in the

places DPP-4 inhibitors as an option for the second component of initial dual or triple

US: sitagliptin (approved 2006), saxagliptin (approved 2009), linagliptin (approved 2011),

therapy in patients with entry HbA1c levels of C7.5% or C9%, respectively. The DPP-4

and alogliptin (approved 2013). Vildagliptin is

inhibitors may also be considered as the first

another DPP-4 inhibitor that has been extensively studied and is currently available

component of dual or triple therapy for patients for whom metformin is contraindicated. The

in the European Union and Japan. There are also other DPP-4 inhibitors in earlier stages of

detailed AACE guidelines issued in 2011 noted that DPP-4 inhibitors, along with metformin,

development that may become available over

sulfonylureas, glinides, and thiazolidinediones,

the coming years. Although all of the DPP-4 inhibitors share the same mechanism of action,

are all approved for use in combination with insulin [3]. However, the guidelines also

they have different chemical pharmacokinetic properties, which

and may

highlight a raised potential for hypoglycemia when a sulfonylurea or a glinide is used with

translate into clinical options with distinct

insulin, as well as several adverse effects

profiles.

associated with thiazolidinediones in combination with insulin, suggesting that

Place in Current Guidelines

these combinations considered.

developed

resistant GLP-1 increasing levels

and

include

In clinical trials, all available DPP-4 inhibitors have been shown to improve glycemic control,

inhibitors

are

placed

should

be

among

carefully

The ADA and EASD also issued a position

with clinically meaningful reductions in HbA1c

statement on the management of hyperglycemia in T2DM [12]. The ADA/EASD

[11]. Furthermore, they are well tolerated, are

guidelines

are

less

prescriptive,

discuss

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Adv Ther (2013) 30:1067–1085

1070

advantages

and

disadvantages

of

all

Use in Patients with Chronic Kidney Disease

antidiabetes medicines, and highlight the need for individualization of treatment. In the general recommendations outlined in the guidelines, DPP-4 inhibitors are positioned alongside sulfonylureas, thiazolidinediones, GLP-1 agonists, and insulin, as a second-line add-on to metformin. They are prioritized along with GLP-1 agonists as an add-on to metformin when the goal is to avoid weight gain, and with GLP-1 agonists and thiazolidinediones when the goal is to avoid hypoglycemia. When metformin is not an option for first-line therapy, the ADA/EASD guidelines suggest a

The National Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative (KDOQI) defines CKD by the presence of kidney damage or a glomerular filtration rate (GFR) \60 mL/ min/1.73 m2 for 3 months or more [18]. It also classifies the stages of CKD as ranging between Stage 1 (kidney damage with normal or increased GFR) and Stage 5 (kidney failure). End-stage renal disease (ESRD) is included under Stage 5 of the KDOQI classification and is defined as irreversible decline in kidney

DPP-4

function that is severe enough to be fatal in the absence of dialysis or transplantation

Among other guidelines, the International

[18]. Diabetes is considered a major risk factor for

sulfonylurea, thiazolidinedione, inhibitor, or GLP-1 agonist.

Diabetes Federation [13], the National Institute for Health and Clinical Excellence [14], and the US Department of Veterans Affairs/Department of Defense [15], all suggest DPP-4 inhibitors as an alternative add-on to metformin, when a sulfonylurea is contraindicated or when hypoglycemia is a concern. Guidelines are typically based on randomized trials that recruit the most straightforward patients. In the past, this is known to have led to underuse of new treatments in the very patients who could benefit the most. For example, African Americans are generally not well represented in clinical trials [16], and this, in addition to other factors, resulted in lower use of angiotensin-converting

enzyme

(ACE)-

inhibitors (ACEI) for the treatment of hypertension in African Americans [17]. Conversely, therapies should not be used in patients when evidence is lacking. Therefore, in light of a number of recently reported studies, it is worthwhile examining the available evidence for use of DPP-4 inhibitors in vulnerable patient groups.

123

CKD, with nearly 40% of adults with T2DM having some degree of CKD [19, 20]. Furthermore, 44% of new ESRD cases in the US in 2010 had a primary diagnosis of diabetes [21]. While managing hyperglycemia is a key goal in patients with CKD, glycemic targets and choice of therapy in this patient group warrant special consideration. For example, metformin, normally the first choice of treatment for T2DM, is renally excreted, and decreased kidney function may increase the risk of lactic acidosis with its use. Current prescribing guidelines in the US contraindicate metformin when serum creatinine levels are C1.4 mg/dL in women and C1.5 mg/dL in men [22]. Furthermore,

many

other

common

antidiabetes drugs are renally excreted and have a prolonged half-life in patients with CKD, thereby increasing the risk of hypoglycemia. Recent guidelines for diabetes and CKD state that HbA1c targets of \7.0% are not recommended in patients with diabetes who are at risk for hypoglycemia, including those treated with insulin or sulfonylureas and/ or who have advanced CKD. They suggest

Adv Ther (2013) 30:1067–1085

1071

instead extending HbA1c targets above 7.0% for

the

patients with diabetes who are at risk of

mediated

hypoglycemia and have clinically significant comorbidities or limited life expectancy [23].

intestinal transport system and related to cytochrome P450 3A4 (CYP3A4) metabolism

The glucose-dependent stimulation of insulin release by the DPP-4 inhibitors confers

have been well characterized, with some variation among the DPP-4 inhibitors [37–41,

a low risk of hypoglycemia [24], suggesting

44]. Generally, the DPP-4 inhibitors have

potential value for managing hyperglycemia in patients with T2DM and CKD. Indeed, a

limited drug–drug interactions via these mechanisms [37–41, 44]. However, alternatives

number of trials that specifically investigated DPP-4 inhibitors in renally impaired

to strong inducers of CYP3A4 or P-gp (e.g. rifampin) are strongly recommended when

populations have been reported (Table 1) or

linagliptin is to be administered [38]. In

completed with results anticipated in the near future (Table 2) [25–36]. Efficacy and safety data

addition, a reduction of the saxagliptin dosage to 2.5 mg once daily is recommended when

from the clinical trials reported to date are encouraging, and the DPP-4 inhibitors were

coadministered with strong inhibitors (e.g. ketoconazole) [39].

generally

well

tolerated

(Table 1).

propensity via

for the

drug–drug

interactions

p-glycoprotein

(P-gp)

CYP3A4/5

With

appropriate caution, the DPP-4 inhibitors can be used in patients with all degrees of renal

Use in African Americans

insufficiency, including ESRD, although dosage reduction is needed for saxagliptin, sitagliptin,

African Americans are at an increased risk of T2DM, with a prevalence of diabetes

and vildagliptin. Linagliptin can be used without adjustment, since it is not renally

approximately double that of the white population [45]. This group also has an

excreted (Table 3) [37–41].

increased rate of complications and greater disability from complications, as well as poorer

Individuals with concomitant T2DM and CKD may be receiving an ACEI for

glycemic control and quality of care [46–50].

management of hypertension because this class of medications may reduce cardiovascular

The pathophysiology of T2DM may be different in African Americans than in other populations,

events and protect the kidney [2]. A small

with studies suggesting that insulin resistance is higher in minority populations [51]. There are

increase in the risk of angioedema has been observed in patients taking concurrent ACEI

various theoretical reasons to consider DPP-4

and vildagliptin, but the authors were unable to determine a class effect through review of

inhibitors in African Americans. First, a small number of studies report racial disparities in

postmarketing

GLP-1 levels that may have implications for efficacy of DPP-4 inhibitors in African

surveillance

data

and

the

literature [42]. It is postulated that ACE inhibition shifts the metabolism of the

Americans. Two studies observed that African

angioedema-associated vasoactive peptides bradykinin and substance P to the secondary

American adolescents had lower GLP-1 concentrations than white adolescents [52, 53].

DPP-4

In contrast, an earlier investigation reported that obese African American adults had

pathway

[42,

43].

However,

little

information is available regarding the clinical relevance and frequency of ACEI and DPP-4 inhibitor interactions [43]. On the other hand,

significantly higher fasting and post-challenge GLP-1 concentrations than obese white adults

123

123

Linagliptin, 5 mg/day

Saxagliptin, 2.5 mg/day

Sitagliptin, 50 mg/day (moderate RI) or 25 mg/day (severe RI)

Sitagliptin, 50 mg/day (moderate RI) or 25 mg/day (severe RI)

Sitagliptin, 25 mg/day

Vildagliptin, 50 mg/day

[29]

[30, 31]

[32]

[33]

[34]

[35, 36]

515 (Ext: 369)

54-week double-blind, randomized, parallel group 24-week double-blind, randomized, placebocontrolled phase; 28-week extension

Moderate/severec (controlled phase included four patients with ESRD on dialysis, two of these patients randomized to vildagliptin entered extension)

54-week double-blind, randomized, activecontrolled

12-week double-blind, randomized, placebocontrolled phase; 42-week activecontrolled extension

Continued (included insulin, insulin and OAD, OAD mono- and combination therapy)

All OADs washed out

Glipizide 2.5 mg/day; titrated to maximum of 20 mg/day Placebo

All OADs washed out

Glipizide 2.5 mg/day; titrated to maximum of 20 mg/day

Extension: glipizide 5 mg/ day; titrated in 2-week intervals to maximum of 20 mg/day

All OADs washed out; ?/insulin continued

Continued (included insulin, insulin and OAD, OAD monotherapy)

Placebo

First phase: placebo

Continued (included insulin, insulin and OAD, OAD mono- and combination therapy; fixed for 12 weeks, adjusted thereafter)

Placebo

52-week double-blind, randomized, placebocontrolled

12-week double-blind, randomized, placebocontrolled phase; 40-week extension

Background therapy

Control

Study design

ESRD, all undergoing dialysis

Moderate/severe, not on dialysisb

426

129

Moderate/severe/ ESRD on dialysisc

Moderate/severe/ ESRD

Severe, not on dialysisb

RI inclusion criteria

91

(Ext: 129)

170

133

Na

Week 54, severe RI: vildagliptin -0.8; placebo -0.07

Week 54, moderate RI: vildagliptin -0.57; placebo -0.13

Week 24, severe RI: vildagliptin -0.91; placebo -0.32

Week 24, moderate RI: vildagliptin -0.74; placebo -0.24

Approximate adjusted mean change from baseline, %e

Week 54: sitagliptin -0.72 (-0.95, -0.48) glipizide -0.87 (-1.11, -0.63)

Mean change from baselined, % (95% CI)

Week 54: sitagliptin -0.8 (-0.9, -0.6) glipizide -0.6 (-0.8, -0.5)

Mean change from baselined, % (95% CI)

Week 54: sitagliptin -0.7 (-0.9, -0.4) Placebo/glipizide: -1.0 (-1.6, -0.3)

Week 12: sitagliptin -0.6 (-0.8, -0.4) Placebo -0.2 (-0.4, 0.1)

Mean change from baseline, % (95% CI)

Week 52: saxagliptin -1.08 (-1.37, -0.80) Placebo -0.36 (-0.63, -0.08)

Week 12: saxagliptin -0.86 (-1.08, -0.64) Placebo -0.44 (-0.66, -0.23)

Adjusted mean change from baseline, % (95% CI)

Week 52: linagliptin -0.71; placebo 0.01

Week 12: linagliptin -0.76; placebo -0.15

Adjusted mean change from baseline, %

Change in HbA1c (reported as in original publication)

b

a

RI renal impairment, HbA1c glycated hemoglobin, OAD oral antidiabetes drug, ext extension, ESRD end-stage renal disease, CI confidence interval N number of randomized participants Degree of RI categorized based on glomerular filtration rate estimated by the Modification of Diet in Renal Disease formula as moderate (C30 to \50 mL/min/1.73 m2) or severe (\30 mL/min/1.73 m2) c Degree of RI categorized based on creatinine clearance (CrCl) estimated by the Cockcroft-Gault formula as moderate (CrCl C30 to \50 mL/min), severe (CrCl; \30 mL/min, and not receiving dialysis), or ESRD (receiving dialysis) d Least squares mean change from baseline e Number in this table estimated from bar graph of adjusted mean change in HbA1c

Study drug

References

Table 1 Prospective phase 2/3 clinical trials of DPP-4 inhibitors in renally impaired patients (with published results)

1072 Adv Ther (2013) 30:1067–1085

NCT01098539

NCT01087502

NCT00740363

Albiglutide/sitagliptin

Linagliptin/placebo and glimepiride

Sitagliptin/placebo

25

241

507

Number enrolled

4-week, open-label, randomized, crossover

12-week, doubleblind, randomized, placebo-controlled phase; 40-week active-controlled extension

26-week, doubleblind, randomized, active-controlled

Design

Age C18 years

New onset diabetes patients with fasting plasma glucose 7–8 mmol/L, and/or 2-h plasma glucose 12–18 mmol/L after an oral glucose tolerance test OR patients already on OAD therapy, but with HbA1c C8.0% and B11.0%

Renal transplant recipient more than 1 year post-transplant with stable renal function and stable prednisolone dose for the last 3 months before inclusion

Age C18 years

BMI B45 kg/m2

HbA1c C7.0% and B10.0%

Patients with T2DM and with GFR \60 mL/min

Fasting C-peptide C0.8 ng/mL (C0.26 nmol/L)

BMI C20 and B45 kg/m2

HbA1c C7.0% and B10.0%

Inadequate glycemic control with diet and exercise, or metformin, thiazolidinediones, sulfonylurea, or any combination of these OADs

Patients with T2DM and RI

Key inclusion criteria

T2DM type 2 diabetes mellitus, RI renal impairment, HbA1c glycated hemoglobin, BMI body mass index, GFR glomerular filtration rate, OAD oral antidiabetes drug

ClinicalTrials identifier

Study drug/comparator

Table 2 Recently completed phase 3/4 trials of DPP-4 inhibitors in renally impaired patients

Adv Ther (2013) 30:1067–1085 1073

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Table 3 Recommended dosing of DPP-4 inhibitors in the presence of CKD

Alogliptin [37]

First approved Standard dose

Recommended dose in context of chronic kidney disease

US (2013)

CrCl C30 to \60 mL/min (moderate RI): 12.5 mg once daily

25 mg once daily

CrCl \30 mL/min (severe/ESRD): 6.25 mg once daily Linagliptin [38]

US (2011)

5 mg once daily

No dose adjustment required

Saxagliptin [39]

US (2009)

5 mg once daily

CrCl B50 mL/min (moderate/severe/ESRD): 2.5 mg once daily

Sitagliptin [40]

US (2006)

100 mg once daily CrCl C30 to \50 mL/min (moderate RI): 50 mg once daily CrCl \30 mL/min (severe/ESRD): 25 mg once daily

Vildagliptin [41] EU (2007)

50 mg twice daily

CrCl \50 mL/min (moderate/severe/ESRD): 50 mg once daily

CrCl creatinine clearance, ESRD end-stage renal disease, RI renal impairment [54]. Further studies are warranted to confirm racial differences in GLP-1 levels and to

information for this population. While the DPP-4 inhibitors seem theoretically

investigate any therapeutic implications.

appropriate for use in African Americans with

In the meantime, there are other reasons why DPP-4 inhibitors may be a good option for this

T2DM, this group is characterized by higher HbA1c levels than other populations [58]. With

population. A significant proportion of African Americans are overweight or obese, with the

predicted HbA1c reductions ranging between 0.4 and 1.0% with this class of drugs [11, 59],

prevalence of overweight and obesity combined

monotherapy would likely not be suitable for all

at 76.6% (69.9% in men, 82.1% in women), and the prevalence of obesity at 49.6% (38.8% in

patients, although larger reductions are expected in patients with higher baseline

men, 58.6% in women) [55]. Overweight and obesity are risk factors for insulin resistance, and

HbA1c [60]. Based on composite analyses of available

all guidelines therefore recommend losing

pharmacokinetic

weight for overweight or obese patients with T2DM [2–4]. In contrast to insulin and some oral

information for all DPP-4 inhibitors state that no dose adjustment is necessary based on race

antidiabetes drugs that can result in weight gain, the weight-neutral DPP-4 inhibitors may

[37–41], but to date only linagliptin has been specifically investigated in African Americans. A

therefore be an appropriate option for patients

phase 1 study (NCT00935220) assessing its

who are overweight or obese. African Americans are also disproportionally affected by CKD and

pharmacodynamic and pharmacokinetic profile in African Americans with T2DM for

ESRD [56, 57], with the rate of new ESRD cases being 3.4 times higher among this group than

7 days, supported linagliptin 5 mg/day as effective for controlling blood glucose levels

among the white population [21]. The presence

[61]. A subsequent phase 3 trial (NCT01194830)

of renal impairment has implications for diabetes management, but as discussed in the

evaluated its efficacy and safety in black/African Americans with T2DM over 24 weeks [62]. In

previous section, the DPP-4 inhibitors remain a viable choice in this setting.

this study, 226 patients were randomized to linagliptin or placebo, and HbA1c levels were

Despite the prevalence of T2DM in African Americans,

123

there

is

limited

clinical

trial

measured

every

data,

6 weeks.

the

A

prescribing

statistically

significant and clinically relevant difference

Adv Ther (2013) 30:1067–1085

1075

between treatment groups was found for the

range of 7.0–7.5% should generally be aimed for

change in HbA1c after 24 weeks [placebo-

in older patients. The caveat to this statement is

adjusted mean change of -0.58% (95% CI 0.91 to -0.26%; P\0.001)], indicating the

that individual comorbidities, and cognitive and functional status, should be considered

superiority of linagliptin compared with placebo in reducing HbA1c in black/African

when determining goals. Furthermore, this position statement highlights hypoglycemia in

American

as

older people as a highly prevalent and under-

expected from pivotal trials, linagliptin was well tolerated and weight neutral, with a low

recognized disorder with severe consequences such as falls, cognitive impairment, and

rate of hypoglycemic events, confirming its safety profile as well as efficacy in African

hospital admission [69]. The heterogeneity of this population is also

American patients with T2DM [63].

addressed

Use in Older People

recommend that the same glycemic targets be applied to otherwise healthy older people as to

The latest census figures in the US indicate that

younger people with diabetes; and a less ambitious target be applied to patients with

patients

[63].

Furthermore,

people aged 65 years and older represent 13.2% of the population [64], and this proportion is

by

the

ADA.

Their

guidelines

more complicated conditions that include

expected to grow to just over 20% by 2050 [65].

multiple comorbidities, a high level of functional dependency, and limited life

The incidence of T2DM in older people is a major public health concern, and in 2010

expectancy [2, 70]. The DPP-4 inhibitors

almost 27% of people aged 65 years and older in the US had diabetes [1]. Clinical

particular interest for the treatment of older patients with T2DM for a number of reasons,

management of the older patient with T2DM is often challenging as these patients have an

namely their convenient oral dosing, the

have

generated

increased prevalence of cardiovascular risk

importance of avoiding hypoglycemia in the elderly, and considerations of declining renal

factors, diabetes-related complications, and comorbidities such as renal impairment,

function in this patient group. Indeed, the recent position statement mentioned above

congestive heart failure, cognitive impairment, and physical disability. Furthermore, they are

states that in selected older patients not at

often prescribed multiple medications, which

target or where there is poor tolerance to glucose-lowering agents, the use of DPP-4

further complicates treatment strategies and may reduce adherence [66–68]. The older

inhibitors can be considered as second-line therapy [69]. The ADA acknowledges the few

T2DM patient population is, however, a highly heterogeneous group with a broad spectrum of

side effects associated with DPP-4 inhibitors in

and

the context of their use in older patients; however, it also notes that their costs may be

comorbidities. A position statement issued by the International Association of Gerontology

a barrier to some older patients [2]. The prescribing information available for these

and Geriatrics (IAGG), the European Diabetes Working Party for Older People (EDWPOP), and

drugs

disease

duration,

life

expectancy,

generally

agree

that

no

overall

the International Task Force of Experts in

differences in safety or effectiveness were observed between patients aged 65 years and

Diabetes, recommends that an HbA1c target

over and younger patients [37–41]. However,

123

Adv Ther (2013) 30:1067–1085

1076

caution is advised in the context of older

well tolerated in elderly patients and no safety

patients,

concerns were identified.

who

are

more

likely

to

have

decreased renal function, and dosing adjustments are recommended for all DPP-

Other pooled analyses, subgroup analyses, and systematic reviews also showed that DPP-4

inhibitors, except circumstances.

these

inhibitors in the older T2DM population were generally effective and well tolerated [74–81].

Three studies that prospectively assessed

However, some studies show that when DPP-4

DPP-4 inhibitors in older patients with T2DM have been reported [71–73] (Table 4). A double-

inhibitors are concomitantly administered with insulin or a sulfonylurea, there is an elevated

blind, randomized, active-controlled study compared vildagliptin with metformin over 24 weeks in 335 drug-naı¨ve patients with

risk of hypoglycemia over the concomitant administration of placebo with insulin or a

T2DM aged C65 years. In this study, 41% of patients had normal renal function, 57% had

analysis evaluating linagliptin as add-on therapy to basal insulin showed no increased

mild renal insufficiency, and less than 2% had moderate renal insufficiency. The investigation

risk of hypoglycemia with the DPP-4 inhibitor [81]. Given the serious consequences of

showed that vildagliptin is an effective and

hypoglycemic events in older patients, the

well-tolerated treatment option in this group, demonstrating non-inferiority to metformin in

combination of a DPP-4 inhibitor with a sulfonylurea is perhaps ill advised; in fact, the

terms of glycemic control, but superior gastrointestinal tolerability [71]. The second

IAGG, EDWPOP, and the International Task Force of Experts in Diabetes recommend that

trial, a double-blind, randomized, placebocontrolled study of sitagliptin over 24 weeks in

sulfonylurea therapy should be avoided in any older patient at risk of hypoglycemia [69].

linagliptin,

under

206 patients with T2DM aged C65 years,

sulfonylurea [82, 83]. In contrast, a pooled

Interestingly,

there

is

also

preliminary

concluded that sitagliptin significantly and rapidly improved glycemic control and was

evidence that DPP-4 inhibitors are associated with a reduced risk of bone fractures compared

well tolerated in this group [72]. This study also included patients with moderate renal

with placebo or other treatments [84]. Recent evidence shows that T2DM is an independent

insufficiency (22%), but excluded those with

risk factor for bone fracture [85, 86] and that

severe renal insufficiency (estimated creatinine clearance \35 mL/min). Finally, a randomized,

older people with T2DM are at an increased risk of hip fractures [87, 88]. Furthermore, clinical

double-blind, placebo-controlled study investigated the efficacy and safety of

trial data suggest that DPP-4 inhibitors may be associated with a lower risk of stroke compared

linagliptin in 241 patients aged C70 years with

with other therapies [89]. Patients with diabetes

T2DM and insufficient glycemic control despite metformin and/or sulfonylurea and/or insulin

have an increased risk of ischemic stroke, a risk that increases in correlation with duration of

therapy [73]. The majority of patients in this study had either normal renal function (21%) or

diabetes [90, 91], therefore posing a particular concern for elderly patients with long-standing

mild renal insufficiency (52%); 26% of patients

T2DM. If confirmed, these risk reductions will

had moderate renal insufficiency and less than 2% had severe renal insufficiency. This study

provide further compelling reasons to consider DPP-4 inhibitors in older patients. Various

concluded that linagliptin was effective and

prospective studies of glycemic outcomes in

123

Vildagliptin, 100 mg/day

Sitagliptin, 100 or 50 mg/day depending on renal function

Linagliptin

[71]

[72]

[73]

C70 yrs

C65 yrs

206

241

C65 yrs

Age inclusion criteria

335

Na

74.9 yrs

72 yrs

71 yrs

Mean age

24-week double-blind, randomized, placebocontrolled, parallel group study

24-week double-blind, randomized, placebocontrolled, parallel group study

24-week double-blind, randomized, activecontrolled, parallel group study

Study design

All OADs washed out

Continued (included metformin, sulfonylureas, or basal insulin, or combinations of these drugs)

Placebo

Patients considered drug-naı¨ve (no OADs for at least 12 weeks prior to screening; no OADs for more than 3 consecutive months at any time in the past)

Background therapy

Placebo

Metformin

Control

HbA1c glycated hemoglobin, yrs years, OAD oral antidiabetes drug, CI confidence interval a N number of randomized participants b Least squares mean change from baseline

Study drug

Ref

Table 4 Prospective phase 2/3 clinical trials of DPP-4 inhibitors in older patients (with published results)

Week 24: linagliptin -0.61 (0.06) Placebo 0.04 (0.07)

Adjusted mean change from baseline, % (SE)

Week 24: sitagliptin -0.5 (-0.7, -0.2) Placebo 0.2 (0.0, 0.5)

Mean change from baselineb, % (95% CI)

Week 24: vildagliptin -0.64 (0.07), (P \ 0.001 vs. baseline) Metformin -0.75 (0.07), (P \ 0.001 vs. baseline)

Adjusted mean change from baseline, % (SE)

Change in HbA1c (reported as in original publication)

Adv Ther (2013) 30:1067–1085 1077

123

123

NCT01006603 (completed)

NCT01183104 (recruiting)

NCT01189890 (completed)

NCT01257451 (completed)

Saxagliptin/ glimepiride

Sitagliptin/ glimepiride

Sitagliptin/ glimepiride

Vildagliptin/ placebo

431

480

900

957

March 2012

October 2012

December 2014

June 2012

24-week, doubleblind, randomized, placebo-controlled

30-week, doubleblind, randomized, active-controlled

52-week, open-label, randomized, activecontrolled

52-week, doubleblind, randomized, active-controlled

(Estimated) (Estimated) Study design number enrolled completion date

Patients with T2DM; HbA1c C7.0% and B10.0% and assessed as inadequately controlled; BMI C19 and B45 kg/m2; age C70 years

Patients with T2DM; community-dwelling; age 65–85 years

Patients with T2DM who are OAD-naı¨ve (or alphaglucosidase or biguanide monotherapy, to be washed out 4 weeks prior to randomization); treatment with diet and exercise for 12 weeks or longer at screening; HbA1c C6.9% and B8.9%; age C60 years

Patients with T2DM treated with stable metformin monotherapy for at least 8 weeks prior to first visit; HbA1c C7.0% and B9.0%; age C65 years

Key inclusion criteria

T2DM type 2 diabetes mellitus, HbA1c glycated hemoglobin, OAD oral antidiabetes drug, BMI body mass index

ClinicalTrials identifier

Study drug/ comparator

Table 5 Planned/recently completed prospective clinical trials of DPP-4 inhibitors in older patients

1078 Adv Ther (2013) 30:1067–1085

(TECOS)

NCT00790205

(SAVOR-TIMI 53) 14,000

7.7-year, double-blind, randomized, active controlled

December 2014 (ongoing)

Patients with T2DM; HbA1c C6.5%; high risk for cardiovascular events

Patients with T2DM; HbA1c C6.5% and B8.5% if treatment-naı¨ve or mono-/dual therapy with metformin and/or alpha-glucosidase inhibitor; HbA1c C6.5% and B7.5% if treatment with sulfonylurea/glinides in mono- or dual therapy with metformin and/or alpha-glucosidase inhibitor; pre-existing cardiovascular disease OR specified diabetes end-organ damage OR age C70 years OR C2 specified cardiovascular risk factors

Patients with T2DM who are drug-naı¨ve or receiving monotherapy or combination antidiabetes therapy; HbA1c C6.5% and B10.0%; high risk of cardiovascular events defined by: (1) albuminuria (UACR C30 mg/g) plus previous macrovascular disease and/or (2) impaired renal function patients with eGFR 15 to \45 mL/min/ 1.73 m2 are eligible with any UACR level, those with eGFR C45–75 mL/min/1.73 m2 are required to have a UACR [200 mg/g)a

4–5-year, double-blind, Patients with T2DM; HbA1c C6.5% and B8.0% on stable randomized, placebodose(s) of antihyperglycemic agent(s), including insulin; precontrolled existing cardiovascular disease

May 2013 4-year, double-blind, (completed) randomized, placebocontrolled

September 2018 (ongoing)

January 2018 4-year, double-blind, (recruiting) randomized, placebocontrolled

T2DM type 2 diabetes mellitus, HbA1c glycated hemoglobin, UACR urinary albumin creatinine ratio, eGFR estimated glomerular filtration rate a Additional study details from https://investor.lilly.com/releasedetail.cfm?ReleaseID=781539

Sitagliptin/ placebo

16,492

NCT01107886

Saxagliptin/ placebo

8,300

6,000

(CARMELINA)

NCT01897532

Linagliptin/ NCT01243424 glimepiride (CAROLINA)

Linagliptin/ placebo

(EXAMINE)

5,380

June 2013 4.75-year, double-blind, Patients with T2DM receiving monotherapy or combination (completed) randomized, placeboantidiabetes therapy; HbA1c C6.5% and B11.0%; HbA1c C7.0% controlled and B11.0% if on insulin; diagnosis of acute coronary syndrome within 15–90 days prior to randomization

NCT00968708

Key inclusion criteria

Alogliptin/ placebo

Study design

(Estimated) completion date

Study drug/ ClinicalTrials (Estimated) comparator identifier (NAME) number enrolled

Table 6 Completed or ongoing clinical trials to investigate effects of DPP-4 inhibitors on cardiovascular morbidity and mortality

Adv Ther (2013) 30:1067–1085 1079

123

Adv Ther (2013) 30:1067–1085

1080

this population are underway or recently

investigate the effects of DPP-4 inhibitors on

completed (Table 5), and their findings will

cardiovascular

provide further valuable safety and efficacy data about DPP-4 inhibitors in this group, and

(Table 6), and provide further insight into the efficacy, safety, and durability of response of

may also allow for additional pooled analyses of outcomes of interest such as fracture.

these drugs. Results from the first two completed trials, EXAMINE and SAVOR-TIMI

Furthermore, ongoing cardiovascular safety

53, demonstrated no change in the risk of the

trials with the DPP-4 inhibitors (see below and Table 6) are expected to include

composite major adverse cardiovascular event endpoint with either alogliptin or saxagliptin

substantial numbers of elderly patients, providing valuable outcome information in

compared with placebo when added to the standard of care [97, 98]. In EXAMINE, the

this

morbidity

and

mortality

particular,

point estimate for the hazard ratio (HR) was \1

patients aged C70 years qualify for inclusion in the CAROLINA (Cardiovascular Outcome

and the upper limit of the 95% CI was \1.3, which was the pre-specified non-inferiority

Study of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes) trial, a large-

safety margin (HR with alogliptin, 0.96; upper boundary of the one-sided repeated CI, 1.16;

scale study that aims to investigate the effects

P\0.001 for non-inferiority) [97]. Similarly in

of linagliptin on cardiovascular morbidity and mortality.

SAVOR-TIMI 53, saxagliptin met the noninferiority criterion but did not demonstrate

Future Directions

cardiovascular superiority versus placebo (HR with saxagliptin 1.00, 95% CI 0.89–1.12,

Safety data for DPP-4 inhibitors based on

P = 0.99 for superiority, P\0.001 for noninferiority) [98].

particular

population.

In

registration studies are reassuring, with various meta-analyses indicating a benign and perhaps beneficial cardiovascular safety profile

CONCLUSIONS

for the class [92–96]. However, their long-term impact on cardiovascular outcomes has yet to

The DPP-4 inhibitors are clearly emerging as a

be firmly established by clinical trials. To address this, several large-scale trials,

useful treatment option in the general T2DM population and, as additional trials are reported,

including

of

it appears their characteristics may make them

Cardiovascular Outcomes with Alogliptin versus Standard of Care), CARMELINA

particularly suitable for more vulnerable patient populations. DPP-4 inhibitors can be used in

(Cardiovascular and Renal Microvascular Outcome Study With Linagliptin in Patients

the context of CKD, a significant consideration for any antidiabetes treatment. They are also

With Type 2 Diabetes Mellitus at High Vascular

weight neutral, an important aspect when

Risk), CAROLINA, SAVOR-TIMI 53 (The Saxagliptin Assessment of Vascular Outcomes

making therapy choices with a patient who is overweight or obese. Furthermore, their

Recorded in Patients with Diabetes Mellitus— Thrombolysis in Myocardial Infarction 53

straightforward dosing and low risk of hypoglycemia are desirable characteristics,

trial), and TECOS (Sitagliptin Cardiovascular

particularly when choosing treatments for older patients.

Outcome

123

EXAMINE

Study),

have

(Examination

been

designed

to

Adv Ther (2013) 30:1067–1085

1081

For various reasons, physicians may be cautious

about

using

new

therapies

in

vulnerable patient populations. However, these groups could potentially benefit from new treatments, and caution can be balanced by close monitoring and vigilance to ensure

conducted studies, and does not involve any new studies of human or animal subjects performed by any of the authors. Open Access. This article is distributed

therapeutic

under the terms of the Creative Commons Attribution Noncommercial License which

advances. Given the variable progression of T2DM and the heterogeneity even within

permits any noncommercial use, distribution, and reproduction in any medium, provided the

subgroups of patients, individualizing therapy will always be essential. Nevertheless, awareness

original author(s) and the source are credited.

that

all

groups

benefit

from

of the typical issues for these high-risk groups may help physicians who are considering therapeutic options, including the DPP-4

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